Gamma-aminobütirik asit tip B (gaba_B) reseptörünün aktivasyonuna i̇lişkin yapisal dinamikler ve alosterik mekanizmalar

Gamma-Aminobutyric Type B Receptor is a member of the Class C G protein–coupled receptor (GPCR) family, functioning through an allosteric mechanism that requires heterodimeric cooperation. Despite advances in structural resolution, the dynamic processes of its function remain insufficiently understood. This thesis develops a detailed framework of the activation pathway and allosteric network from a structural dynamics perspective. We employed a computational strategy integrating Gaussian Network Model–Transfer Entropy (GNM-TE), ANM co-vibrational mode analysis, and Anisotropic Network Model–Langevin Dynamics (ANM-LD). GNM-TE revealed that the global allosteric mechanism is coordinated mainly through domain interfaces, mapping entropy flow regimes across states and highlighting roles of functional sites and pathogenic mutations. Co-vibrational modes showed that isolated subunits lack the intrinsic dynamics for full activation, requiring inter-subunit interactions for coordinated allosteric transitions. ANM-LD simulations generated transition states along the activation path. Distinct features of G-protein–coupled and PAM-bound states, including differences in key modes and cross-correlations, were identified. Overall, structural elements for ligand binding, dimerization, and G-protein coupling display state-dependent dynamics, and the complete heterodimeric assembly is essential for the global motions underlying activation. These findings provide transferable insights for Class C GPCRs, with implications for allosteric modulator design and therapeutic targeting.